This proposal is focused on a clinically important area where we can once again have an immediate impact;preventing surgery-induced microembolic injury to the brain. Air and lipid microemboli enter the circulation during both cardiac and orthopedic surgery, causing ischemia, endothelial dysfunction, and inflammation. These emboli may occlude vessels or they can be extruded through the vascular bed and irritate the endothelium, resulting in acute and chronic neurologic, renal, and splanchnic injury. Our studies show that during cardiac surgery the major source of the lipid microemboli is from the blood salvaged from the surgical field and returned to the patient. Air emboli can come from several sources, such as from cannulae or foam in the blood. In the brain, the passage of microemboli causes blood-brain barrier (BBB) breakdown, and in other vascular beds it is associated with the systemic inflammatory response syndrome. Magnetic resonance imaging (MRI) studies reveal one out of three patients may suffer a new brain lesion following cardiac procedures. In orthopedic patients, during the pressurization of the medullary canal, fat from the bone marrow is extruded into the venous circulation. The fat embolization may cause acute respiratory distress syndrome, neurologic dysfunction, or death. We will use our dog model of cardiac surgery to study brain injury from lipid and air emboli. We will investigate air emboli introduced into the cardiopulmonary bypass (CPB) circuit in two locations, in three forms: air in the venous cannula;agitated air in water in the arterial line;and agitated air in blood (protein-coated gaseous microemboli;foam) in the arterial line. We will investigate whether air emboli can be prevented during open heart surgery by flooding the operative field with argon, a low partial pressure gas. We will also determine whether knee prosthesis surgery using a state of the art reaming system, with chilling and rinse- vacuum methodology is safer than traditional bone reaming. The outcomes will include: brain edema;intravital visualization and recording of intravascular emboli;BBB leakage into the cerebrospinal fluid;emboli count in the CPB circuit, carotid artery, and jugular vein using the EDAC. Quantifier;cerebral blood flow;stereological analysis of vascular endothelial tight junctions;quantification of brain tissue hypoxia (HIF-1);quantification of cellular stress (Hsp70);emboli counts in the brain, lungs, and kidneys;and lipid microemboli in blood samples. We will perform MRI on six groups of dogs which simulate surgical embolic events. Histological evidence will be compared to MRI studies to evaluate the MRI resolution, specificity, and sensitivity to detect the damage from emboli. The MRI analyses will include diffusion-weighted imaging (DWI), spin echo T1, and fast spin echo T2. PUBLIC HEALTH RELEVANCE: We will perform experimental cardiac and orthopedic surgeries in dogs that should provide evidence that certain surgical innovations can reduce the incidence of brain injury and even death. We expect these surgical innovations to reduce the amount of air and fat emboli that enter the bloodstream and circulate to the brain.